| Project/Area Number |
18591079
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Hematology
|
|---|
| Research Institution | Tokyo Medical and Dental University |
|---|
Principal Investigator |
NAKAMOTO Tetsuya Tokyo Medical and Dental University, Department of Rheumatology, COE member (90334383)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
KATO Takayuki Osaka City Universit, Department of Physiology, Assistant Professor (50343413)
|
|---|
| Project Period (FY) |
2006 – 2007
|
| Project Status |
Completed (Fiscal Year 2007)
|
| Budget Amount *help |
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
|
|---|
| Keywords | immunology / Signal Transduction / inflammatory cells / cell adhesion |
|---|
| Research Abstract |
We investigated how proteins of integrin signaling pathway are involved in inflammation.
Cas-L/Hef1/Nedd9 is a member of p 130cas family proteins that are involved in integrin signaling. Although the roles of Cas-L in lymphocytes are reported, its expression in granulocytes was not known. We first showed the expression of Cas-L protein in neutrophils. Tyrosine phosphorylation of Cas-L was observed with the stimulation by LPS, TNF, or fMLP. The tyrosine phosphorylation was enhanced with the adhesion of neutrophils. Granulocytes from Cas-L deficient mice showed enhanced migration in response to fMLP.
CIZ is a nucleo-cytoplasmic shuttling protein that binds to p 130Cas and transcriptionally regulates collagens and matrix metalloproteinases. We screened for new binding partners of CIZ. CIZ binds to the C-terminal domain of collagens in the nucleus, suggesting the transcriptional regulation of collagens by this complex.
We applied the serum-induced arthritis model to CIZ-deficient mice. CIZ deficiency reduced arthritis severity to half of that in wild-type mice. CIZ deficiency reduced inflammatory cell invasion and cartilage destruction. CIZ deficiency suppressed the arthritis-induced increase in the number of osteoclasts in the joint, urinary deoxypyridinoline, and mRNA expression of RANKL. Arthritis-induced increase of mRNA expression of MMP-3, a target of CIZ as a transcription factor, was decreased by CIZ deficiency together with the mRNA expression of Adamts4, IL-1β, and CXCL16. These results suggest that CIZ plays pivotal roles in the induction of inflammatory genes.
|
